Patent Application
20250206699
Provided herein are lipid compounds. Also provided are lipid nanoparticles, each comprising a lipid compound.
Lipid nanoparticles (LNPs) are a promising delivery vehicle for a variety of therapeutic agents, including small molecule drugs, proteins, and nucleic acids. Akinc et al., Nat. Nanotechnol. 2019, 14, 1084-87; Hou et al., Nat. Rev. Mater. 2021, 6, 1078-94. The two FDA-approved COVID-19 mRNA vaccines, mRNA-1273 and BNT162b, employ lipid nanoparticles for antigen mRNA delivery. Polack et al., N. Engl. J. Med 2020, 383, 2603-15; Baden et al., N. Engl. J. Med. 2021, 384, 403-16. However, it remains challenging to deliver a therapeutic agent efficiently, especially a highly charged nucleic acid, such as an mRNA. Weng et al., Biotechnol. Adv. 2020, 40, 107534; Hou et al., Nat. Rev. Mater. 2021, 6, 1078-94. To achieve therapeutic effects, for example, a highly charged mRNA molecules have to reach specific target cells and produce sufficient proteins of interest. Hou et al., Nat. Rev. Mater. 2021, 6, 1078-94. Therefore, there is a need for a lipid compound for delivering a therapeutic agent efficiently.
Provided herein is a compound of Formula (I):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:
Additionally, provided herein is a lipid nanoparticle comprising a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and biochemistry described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
The term “alkyl” refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkyl groups are also referred as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., n-propyl and isopropyl), butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl).
The terms “alkylene” and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally be substituted with one or more substituents Q as described herein. For example, C1-6 alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C1-30), 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkanediyl groups are also referred as “lower alkanediyl.” Examples of alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane-1,1-diyl and ethane-1,2-diyl), propanediyl (including all isomeric forms, e.g., propane-1,1-diyl, propane-1,2-diyl, and propane-1,3-diyl), butanediyl (including all isomeric forms, e.g., butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, and butane-1,4-diyl), pentanediyl (including all isomeric forms, e.g., pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl, and pentane-1,5-diyl), and hexanediyl (including all isomeric forms, e.g., hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, —C(O)CH2—, —C(O)(CH2)2—, —C(O)(CH2)3—, —C(O)(CH2)4—, —C(O)(CH2)5—, —C(O)(CH2)6—, —C(O)(CH2)7—, —C(O)(CH2)8—, —C(O)(CH2)9—, —C(O)(CH2)10—, —C(O)CH2C(O)—, —C(O)(CH2)2C(O)—, —C(O)(CH2)3C(O)—, —C(O)(CH2)4C(O)—, or —C(O)(CH2)5C(O)—.
The term “heteroalkyl” refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkyl groups are also referred as “lower heteroalkyl.” Examples of heteroalkyl groups include, but are not limited to, —OCH3, —OCH2CH3, —CH2OCH3, —NHCH3, —ONHCH3, —NHOCH3, —SCH3, —CH2NHCH2CH3, and —NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, —CH2NHC(O)CH3 and —NHC(O)CH2CH3.
The terms “heteroalkylene” and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms in its main chain, each independently selected from O, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C1-6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkylene groups are also referred as “lower heteroalkylene.” Examples of heteroalkylene groups include, but are not limited to, —CH2O—, —(CH2)2O—, —(CH2)3O—, —(CH2)4O—, —(CH2)5O—, —(CH2)6O—, —(CH2)7O—, —(CH2)8O—, —(CH2)9O—, —(CH2)10O—, —CH2OCH2—, —CH2CH2O—, —(CH2CH2O)2—, —(CH2CH2O)3—, —(CH2CH2O)4—, —(CH2CH2O)5—, —CH2NH—, —CH2NHCH2—, —CH2CH2NH—, —CH2S—, —CH2SCH2—, and —CH2CH2S—. Examples of substituted heteroalkylene groups include, but are not limited to, —C(O)CH2O—, —C(O)(CH2)2O—, —C(O)(CH2)3O—, —C(O)(CH2)4O—, —C(O)(CH2)5O—, —C(O)(CH2)6O—, —C(O)(CH2)7O—, —C(O)(CH2)8O—, —C(O)(CH2)9O—, —C(O)(CH2)10O—, —C(O)CH2OCH2CH2O—, —C(O)CH2O(CH2CH2O)2—, —C(O)CH2O(CH2CH2O)3—, —C(O)CH2O(CH2CH2O)4, —C(O)CH2O(CH2CH2O)5—, —CH2NHC(O)CH2—, or —CH2CH2C(O)NH—.
The term “alkenyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s). The alkenyl is optionally substituted with one or more substituents Q as described herein. The term “alkenyl” embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-45), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen-1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms, e.g., buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).
The terms “alkenylene” and “alkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s). The alkenediyl is optionally substituted with one or more substituents Q as described herein. The term “alkenediyl” embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “F” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 alkenediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenediyl groups include, but are not limited to, ethenediyl (including all isomeric forms, e.g., ethene-1,1-diyl and ethene-1,2-diyl), propenediyl (including all isomeric forms, e.g., 1-propene-1,1-diyl, 1-propene-1,2-diyl, and 1-propene-1,3-diyl), butenediyl (including all isomeric forms, e.g., 1-butene-1,1-diyl, 1-butene-1,2-diyl, and 1-butene-1,4-diyl), pentenediyl (including all isomeric forms, e.g., 1-pentene-1,1-diyl, 1-pentene-1,2-diyl, and 1-pentene-1,5-diyl), and hexenediyl (including all isomeric forms, e.g., 1-hexene-1,1-diyl, 1-hexene-1,2-diyl, 1-hexene-1,3-diyl, 1-hexene-1,4-diyl, 1-hexene-1,5-diyl, and 1-hexene-1,6-diyl).
The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynyl group does not contain a carbon-carbon double bond. The alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), propynyl (including all isomeric forms, e.g., 1-propynyl (—C≡CCH3) and propargyl (—CH2C≡CH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl).
The terms “alkynylene” and “alkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynylene group does not contain a carbon-carbon double bond. The alkynediyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6 alkynediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30), 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, e.g., 1-propyne-1,3-diyl and 1-propyne-3,3-diyl), butynediyl (including all isomeric forms, e.g., 1-butyne-1,3-diyl, 1-butyne-1,4-diyl, and 2-butyne-1,1-diyl), pentynediyl (including all isomeric forms, e.g., 1-pentyne-1,3-diyl, 1-pentyne-1,4-diyl, and 2-pentyne-1,1-diyl), and hexynediyl (including all isomeric forms, e.g., 1-hexyne-1,3-diyl, 1-hexyne-1,4-diyl, and 2-hexyne-1,1-diyl).
The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl is a saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic group. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In still another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.
The term “aryl” refers to a monovalent monocyclic aromatic hydrocarbon radical and/or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (C6-15), or from 6 to 10 (C6-10) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, the aryl is tricyclic. In still another embodiment, the aryl is polycyclic. In certain embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.
The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.
The term “heteroaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring. For a heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. In one embodiment, the heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl is bicyclic. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, e.g., imidazo[2,1-b]thiazolyl and imidazo[4,5-d]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, e.g., 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, e.g., oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, e.g., pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, e.g., [1,2,5]thiadiazolo[3,4-d]pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thienopyridyl (including all isomeric forms, e.g., thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[3,2-c]pyridinyl). In yet another embodiment, the heteroaryl is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.
The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For a heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]-oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.
The term “halogen,” “halide,” or “halo” refers to fluoro, chloro, bromo, and/or iodo.
The term “optionally substituted” is intended to mean that a group or substituent, such as an alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl group, may be substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, each of which is independently selected from, e.g., (a) deuterium (-D), cyano (—CN), halo, imino (═NH), nitro (—NO2), and oxo (═O); (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(O)SRa, —C(NRa)NRbRc, —C(S)Ra, —C(S)ORa, —C(S)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(O)SRa, —OC(NRa)NRbRc, —OC(S)Ra, —OC(S)ORa, —OC(S)NRbRc, —OP(O)(ORb)ORc, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(O)SRd, —NRaC(NRd)NRbRc, —NRaC(S)Rd, —NRaC(S)ORd, —NRaC(S)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa. As used herein, all groups that can be substituted are “optionally substituted.”
In one embodiment, each Qa is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, —C(S)Re, —C(S)ORe, —C(S)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(O)SRe, —OC(NRe)NRfRg, —OC(S)Re, —OC(S)ORe, —OC(S)NRfRg, —OP(O)(ORf)ORg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, —NfRg, —NC(O)Rh, —NReC(O)ORf, —NReC(O)NRfRg, —NReC(O)SRf, —NReC(NRh)NRfRg, —NReC(S)Rh, —NReC(S)ORf, —NReC(S)NRfRg, —NReS(O)Rh, —NeS(O)2Rh, —NReS(O)NRfRg, —NReS(O)2NRfRg, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRfRg, and —S(O)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
In certain embodiments, “optically active” and “enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.
In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center(s). The (+) and (−) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (−) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (−), is not related to the absolute configuration of the compound, R and S.
The term “isotopically enriched” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (H), deuterium (2H), tritium (3H), carbon-11 (11C), carbon-12 (2C), carbon-13 (3C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35Cl), chlorine-36 (36Cl), chlorine-37 (37Cl), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an isotopically enriched compound is in a stable form, that is, non-radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon-12 (12C), carbon-13 (13C), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), phosphorus-31 (31P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-36 (36S), chlorine-35 (35Cl), chlorine-37 (37Cl), bromine-79 (79Br), bromine-81 (81Br), and iodine-127 (127I). In certain embodiments, an isotopically enriched compound is in an unstable form, that is, radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (11C), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), oxygen-15 (15O), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P) sulfur-35 (35S), chlorine-36 (36Cl), iodine-123 (123I), iodine-125 (121I), iodine-129 (129I), and iodine-131 (131I). It will be understood that, in a compound as provided herein, any hydrogen can be 2H, as example, or any carbon can be 13C, as example, or any nitrogen can be 15N, as example, or any oxygen can be 18O, as example, where feasible according to the judgment of one of ordinary skill in the art.
The term “isotopic enrichment” refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope (e.g., 1H for protium or hydrogen-1) of the element. As used herein, when an atom at a particular position in a molecule is designated as a particular less prevalent isotope, it is understood that the abundance of that isotope at that position is substantially greater than its natural abundance.
The term “isotopic enrichment factor” refers the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.
The term “hydrogen” or the symbol “H” refers to the composition of naturally occurring hydrogen isotopes, which include protium (1H), deuterium (2H or D), and tritium (3H), in their natural abundances. Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%. Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.
The term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).
The term “carbon” or the symbol “C” refers to the composition of naturally occurring carbon isotopes, which include carbon-12 (12C) and carbon-13 (13C) in their natural abundances. Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%. Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.
The term “carbon-13 enrichment” or “13C enrichment” refers to the percentage of incorporation of carbon-13 at a given position in a molecule in the place of carbon. For example, carbon-13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon-13 at the specified position. Because the naturally occurring distribution of carbon-13 is about 1.11% on average, carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon-13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).
The terms “substantially pure” and “substantially homogeneous” mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance. In certain embodiments, “substantially pure” or “substantially homogeneous” refers to a collection of molecules, wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular less prevalent isotope, a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound. Thus, for a deuterated compound that has an atom at a particular position designated as deuterium, a compound that contains a protium at the same position is an impurity.
The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
For a divalent group described herein, no orientation is implied by the direction in which the divalent group is presented. For example, unless a particular orientation is specified, the formula —C(O)O— represents both —C(O)O— and —OC(O)—.
The phrase “an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof” has the same meaning as the phrase “(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, or hydrate of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, or hydrate of an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein.”
In one embodiment, provided herein is a compound of Formula (I):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
In certain embodiments, in Formula (I), U and V are each —C(O)O—; X and Z are each C(H); and R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more substituents Q. In certain embodiments, in Formula (I), U and V are each —C(O)O—; X and Z are each C(H); and R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more halo. In certain embodiments, in Formula (I), U and V are each —C(O)O—; X and Z are each C(H); and R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more fluoro. In certain embodiments, in Formula (I), U and V are each —C(O)O—; X and Z are each C(H); and R1, R2, R3, or R4 is C1-20 alkyl, substituted with one, two, or three fluoro.
In certain embodiments, in Formula (I), U and V are each —C(O)O—; X and Z are each C(H); and L1 or L2 is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), U and V are each —C(O)O—; X and Z are each C(H); and L1 or L2 is unsubstituted C1-20 heteroalkylene. In certain embodiments, in Formula (I), U and V are each —C(O)O—; X and Z are each C(H); and L1 and L2 are each independently —NH—C1-20 alkylene or —NH—C1-20 heteroalkylene, each optionally substituted with one or more substituents Q.
In certain embodiments, in Formula (I), U and V are each —C(O)O—; X and Z are each C(H); R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more substituents Q; and L1 or L2 is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), U and V are each —C(O)O—; X and Z are each C(H); R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more halo; and L1 or L2 is unsubstituted C1-20 heteroalkylene. In certain embodiments, in Formula (I), U and V are each —C(O)O—; X and Z are each C(H); R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more fluoro; and L1 or L2 is unsubstituted C1-20 heteroalkylene. In certain embodiments, in Formula (I), U and V are each —C(O)O—; X and Z are each C(H); R1, R2, R3, or R4 is C1-20 alkyl, substituted with one, two, or three fluoro; and L1 or L2 is unsubstituted C1-20 heteroalkylene.
In certain embodiments, in Formula (I), U and V are each —C(O)—; X and Z are each C(H); and L1 and L2 are each independently C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), U and V are each —C(O)—; X and Z are each C(H); and L1 and L2 are each independently unsubstituted C1-20 heteroalkylene. In certain embodiments, in Formula (I), U and V are each —C(O)—; X and Z are each C(H); and L1 and L2 are each independently —NH—C1-20 alkylene or —NH—C1-20 hetero-alkylene, each optionally substituted with one or more substituents Q.
In one embodiment, in Formula (I),
In another embodiment, in Formula (I),
In yet another embodiment, in Formula (I),
In yet another embodiment, in Formula (I),
In yet another embodiment, in Formula (I),
In yet another embodiment, in Formula (1),
In yet another embodiment, in Formula (I),
In still another embodiment, in Formula (I),
In one embodiment, in Formula (I),
In another embodiment, in Formula (I),
In yet another embodiment, in Formula (I),
In still another embodiment, in Formula (I),
In another embodiment, provided herein is a compound of Formula (II):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein U and V are each independently —C(O)— or —C(O)O—; and R1, R2, R3, R4, R5, L1, L2, and L3 are each as defined herein.
In one embodiment, in Formula (II),
In another embodiment, in Formula (11),
In yet another embodiment, in Formula (II),
In yet another embodiment, in Formula (II),
In yet another embodiment, in Formula (11),
In yet another embodiment, in Formula (II),
In yet another embodiment, in Formula (II),
In still another embodiment, in Formula (II),
In yet another embodiment, provided herein is a compound of Formula (III):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R2, R3, R4, R5, L1, L2, and L3 are each as defined herein.
In yet another embodiment, provided herein is a compound of Formula (IV):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R4, R5, L1, L2, and L3 are each as defined herein.
In one embodiment, in Formula (III) or (IV),
In another embodiment, in Formula (III) or (IV),
In yet another embodiment, in Formula (III) or (IV),
In yet another embodiment, in Formula (111) or (IV),
In yet another embodiment, in Formula (III) or (IV),
In yet another embodiment, in Formula (III) or (IV),
In yet another embodiment, in Formula (III) or (IV),
In still another embodiment, in Formula (III) or (IV),
In yet another embodiment, provided herein is a compound of Formula (V):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein U and V are each independently —C(O)—, —C(O)O—, or —OC(O)O—; and R1, R2, R3, R4, R5, L1, L2, and L3 are each as defined herein.
In one embodiment, in Formula (V),
In another embodiment, in Formula (V),
In yet another embodiment, in Formula (V),
In yet another embodiment, in Formula (V),
In yet another embodiment, in Formula (V),
In yet another embodiment, in Formula (V),
In yet another embodiment, in Formula (V),
In still another embodiment, in Formula (V),
In one embodiment, in Formula (V),
In another embodiment, in Formula (V),
In yet another embodiment, in Formula (V),
In still another embodiment, in Formula (V),
In certain embodiments, in Formula (V), U and V are each —C(O)O—; and R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more substituents Q. In certain embodiments, in Formula (V), U and V are each —C(O)O—; and R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more halo. In certain embodiments, in Formula (V), U and V are each —C(O)O—; and R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more fluoro. In certain embodiments, in Formula (V), U and V are each —C(O)O—; and R1, R2, R3, or R4 is C1-20 alkyl, substituted with one, two, or three fluoro.
In certain embodiments, in Formula (V), U and V are each —C(O)O—; and L1 or L2 is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (V), U and V are each —C(O)O—; and L1 or L2 is unsubstituted C1-20 heteroalkylene. In certain embodiments, in Formula (V), U and V are each —C(O)O—; X and Z are each C(H); and L1 and L2 are each independently —NH—C1-20 alkylene or —NH—C1-20 hetero-alkylene, each optionally substituted with one or more substituents Q.
In certain embodiments, in Formula (V), U and V are each —C(O)O—; R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more substituents Q; and L1 or L2 is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (V), U and V are each —C(O)O—; R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more halo; and L1 or L2 is unsubstituted C1-20 heteroalkylene. In certain embodiments, in Formula (V), U and V are each —C(O)O—; R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more fluoro; and L1 or L2 is unsubstituted C1-20 heteroalkylene. In certain embodiments, in Formula (V), U and V are each —C(O)O—; R1, R2, R3, or R4 is C1-20 alkyl, substituted with one, two, or three fluoro; and L1 or L2 is unsubstituted C1-20 heteroalkylene.
In certain embodiments, in Formula (V), U and V are each —C(O)—; X and Z are each C(H); and L1 and L2 are each independently C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (V), U and V are each —C(O)—; X and Z are each C(H); and L1 and L2 are each independently unsubstituted C1-20 heteroalkylene. In certain embodiments, in Formula (V), U and V are each —C(O)—; X and Z are each C(H); and L1 and L2 are each independently —NH—C1-20 alkylene or —NH—C1-20 hetero-alkylene, each optionally substituted with one or more substituents Q.
In yet another embodiment, provided herein is a compound of Formula (VI):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R1, R2, R3, R4, R5, L1, L2, and L3 are each as defined herein.
In yet another embodiment, provided herein is a compound of Formula (VII):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1, R2, R3, R4, R5, L1, L2, and L3 are each as defined herein.
In yet another embodiment, provided herein is a compound of Formula (VIII):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or a hydrate thereof; wherein R1, R2, R3, R4, R5, L1, L2, and L3 are each as defined herein.
In one embodiment, in Formula (VI), (VII), or (VIII),
In another embodiment, in Formula (VI), (VII), or (VIII),
In yet another embodiment, in Formula (VI), (VII), or (VIII),
In yet another embodiment, in Formula (VI), (VII), or (VIII),
In yet another embodiment, in Formula (VI), (VII), or (VIII),
In yet another embodiment, in Formula (VI), (VII), or (VIII),
In yet another embodiment, in Formula (VI), (VII), or (VIII),
In still another embodiment, in Formula (VI), (VII), or (VIII),
In one embodiment, in Formula (VIII),
In another embodiment, in Formula (VIII),
In yet another embodiment, in Formula (VIII),
In still another embodiment, in Formula (VIII),
In certain embodiments, in Formula (VI), (VII), or (VIII), R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more substituents Q. In certain embodiments, in Formula (VI), (VII), or (VIII), R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more halo. In certain embodiments, in Formula (VI), (VII), or (VIII), R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more fluoro. In certain embodiments, in Formula (VI), (VII), or (VIII), R1, R2, R3, or R4 is C1-20 alkyl, substituted with one, two, or three fluoro.
In certain embodiments, in Formula (VI), (VII), or (VIII), L1 or L2 is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (VI), (VII), or (VIII), L1 or L2 is unsubstituted C1-20 heteroalkylene. In certain embodiments, in Formula (VIII), L1 and L2 are each independently —NH—C1-20 alkylene or —NH—C1-20 heteroalkylene, each optionally substituted with one or more substituents Q.
In certain embodiments, in Formula (VI), (VII), or (VIII), R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more substituents Q; and L1 or L2 is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (VI), (VII), or (VIII), R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more halo; and L1 or L2 is unsubstituted C1-20 heteroalkylene. In certain embodiments, in Formula (VI), (VII), or (VIII), R1, R2, R3, or R4 is C1-20 alkyl, substituted with one or more fluoro; and L1 or L2 is unsubstituted C1-20 heteroalkylene. In certain embodiments, in Formula (VI), (VII), or (VIII), R1, R2, R3, or R4 is C1-20 alkyl, substituted with one, two, or three fluoro; and L1 or L2 is unsubstituted C1-20 heteroalkylene.
In yet another embodiment, provided herein is a compound of Formula (IX):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or a hydrate thereof; wherein:
In still another embodiment, provided herein is a compound of Formula (X):
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or a hydrate thereof; wherein R1, R2, R3, R4, R5, R1a, R2a, L3, L1a, and L2a are each as defined herein.
In one embodiment, in Formula (IX) or (X),
In another embodiment, in Formula (IX) or (X),
In yet another embodiment, in Formula (IX) or (X),
In still another embodiment, in Formula (IX) or (X),
The groups, R1, R2, R3, R4, R5, R1a, R2a, L1, L2, L3, L1a, L2a, U, V, X, and Z, in formulae described herein, including Formulae (I) to (X), are further defined in the embodiments described herein. All combinations of the embodiments provided herein for such groups are within the scope of this disclosure.
In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R1 is unsubstituted C1-20 alkyl. In certain embodiments, R1 is C1-20 alkyl, substituted with one or more substituents Q. In certain embodiments, R1 is C1-20 alkyl, substituted with one or more halo. In certain embodiments, R1 is C1-20 alkyl, substituted with one or more fluoro. In certain embodiments, R1 is C1-20 alkyl, substituted with one, two, or three fluoro.
In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is C1-10 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R1 is unsubstituted C1-10 alkyl. In certain embodiments, R1 is C1-10 alkyl, substituted with one or more substituents Q. In certain embodiments, R1 is C1—.1 alkyl, substituted with one or more halo. In certain embodiments, R1 is C1-10 alkyl, substituted with one or more fluoro. In certain embodiments, R1 is C1-10 alkyl, substituted with one, two, or three fluoro.
In certain embodiments, R1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1 is butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, each optionally substituted with one or more substituents Q.
In certain embodiments, R1 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1 is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each optionally substituted with one or more substituents Q.
In certain embodiments, R1 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each of which is unsubstituted. In certain embodiments, R1 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each of which is unsubstituted. In certain embodiments, R1 is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each of which is unsubstituted.
In certain embodiments, R1 is trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluorotetradecyl, trifluoro-pentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluorooctadecyl, trifluorononadecyl, or trifluoroeicosyl. In certain embodiments, R1 is trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, or trifluorodecyl. In certain embodiments, R1 is trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, or trifluorodecyl.
In certain embodiments, R1 is trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-prop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13-trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16-trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19-trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl. In certain embodiments, R1 is trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, or 10,10,10-trifluorodec-1-yl. In certain embodiments, R1 is 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, or 10,10,10-trifluorodec-1-yl.
In certain embodiments, R1 is C1-20 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R1 is 2-(2-(pentyloxy)ethoxy)ethyl or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl. In certain embodiments, R1 is C2-20 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R1 is C2-20 alkynyl, optionally substituted with one or more substituents Q.
In certain embodiments, R1 is hydrogen, hexyl, octyl, decyl, trifluorohexyl, trifluorooctyl, or trifluorodecyl. In certain embodiments, R1 is hydrogen, n-hexyl, n-octyl, n-decyl, 6,6,6-trifluorohex-1-yl, 8,8,8-trifluorooct-1-yl, or 10,10,10-trifluorodec-1-yl. In certain embodiments, R1 is hydrogen, n-hexyl, n-octyl, 6,6,6-trifluorohex-1-yl, or 8,8,8-trifluorooct-1-yl. In certain embodiments, R1 is hydrogen, n-octyl, n-decyl, 8,8,8-trifluorooct-1-yl, or 10,10,10-trifluorodec-1-yl. In certain embodiments, R1 is hydrogen, n-hexyl, n-octyl, n-decyl, 6,6,6-trifluorohex-1-yl, 8,8,8-trifluorooct-1-yl, 10,10,10-trifluorodec-1-yl, 2-(2-(pentyloxy)ethoxy)-ethyl, or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl. In certain embodiments, R1 is hydrogen, n-hexyl, n-octyl, 6,6,6-trifluorohex-1-yl, 8,8,8-trifluorooct-1-yl, 2-(2-(pentyloxy)ethoxy)-ethyl, or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl. In certain embodiments, R1 is hydrogen, n-octyl, n-decyl, 8,8,8-trifluorooct-1-yl, 10,10,10-trifluorodec-1-yl, 2-(2-(pentyloxy)ethoxy)-ethyl, or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl.
In certain embodiments, R2 is C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is unsubstituted C1-20 alkyl. In certain embodiments, R2 is C1-20 alkyl, substituted with one or more substituents Q. In certain embodiments, R2 is C1-20 alkyl, substituted with one or more halo. In certain embodiments, R2 is C1-20 alkyl, substituted with one or more fluoro. In certain embodiments, R2 is C1-20 alkyl, substituted with one, two, or three fluoro.
In certain embodiments, R2 is C1-10 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is unsubstituted C1-10 alkyl. In certain embodiments, R2 is C1-10 alkyl, substituted with one or more substituents Q. In certain embodiments, R2 is C1-10 alkyl, substituted with one or more halo. In certain embodiments, R2 is C1-10 alkyl, substituted with one or more fluoro. In certain embodiments, R2 is C1-10 alkyl, substituted with one, two, or three fluoro.
In certain embodiments, R2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2 is butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, each optionally substituted with one or more substituents Q.
In certain embodiments, R2 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each optionally substituted with one or more substituents Q. In certain embodiments, R2 is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each optionally substituted with one or more substituents Q.
In certain embodiments, R2 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each of which is unsubstituted. In certain embodiments, R2 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each of which is unsubstituted. In certain embodiments, R2 is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each of which is unsubstituted.
In certain embodiments, R2 is trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluorotetradecyl, trifluoro-pentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluorooctadecyl, trifluorononadecyl, or trifluoroeicosyl. In certain embodiments, R2 is trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, or trifluorodecyl. In certain embodiments, R2 is trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, or trifluorodecyl.
In certain embodiments, R2 is trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-prop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13-trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16-trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19-trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl. In certain embodiments, R2 is trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, or 10,10,10-trifluorodec-1-yl. In certain embodiments, R2 is 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, or 10,10,10-trifluorodec-1-yl.
In certain embodiments, R2 is C1-20 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is 2-(2-(pentyloxy)ethoxy)ethyl or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl. In certain embodiments, R2 is C2-20 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R2 is C2-20 alkynyl, optionally substituted with one or more substituents Q.
In certain embodiments, R2 is hexyl, octyl, decyl, trifluorohexyl, trifluorooctyl, or trifluorodecyl. In certain embodiments, R2 is n-hexyl, n-octyl, n-decyl, 6,6,6-trifluorohex-1-yl, 8,8,8-trifluorooct-1-yl, or 10,10,10-trifluorodec-1-yl. In certain embodiments, R2 is n-octyl, n-decyl, 8,8,8-trifluorooct-1-yl, or 10,10,10-trifluorodec-1-yl. In certain embodiments, R2 is n-hexyl, n-octyl, n-decyl, 6,6,6-trifluorohex-1-yl, 8,8,8-trifluorooct-1-yl, 10,10,10-trifluorodec-1-yl, 2-(2-(pentyloxy)ethoxy)ethyl, or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl. In certain embodiments, R2 is n-octyl, n-decyl, 8,8,8-trifluorooct-1-yl, 10,10,10-trifluorodec-1-yl, 2-(2-(pentyloxy)ethoxy)ethyl, or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl.
In certain embodiments, R3 is C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R3 is unsubstituted C1-20 alkyl. In certain embodiments, R3 is C1-20 alkyl, substituted with one or more substituents Q. In certain embodiments, R3 is C1-20 alkyl, substituted with one or more halo. In certain embodiments, R3 is C1-20 alkyl, substituted with one or more fluoro. In certain embodiments, R3 is C1-20 alkyl, substituted with one, two, or three fluoro.
In certain embodiments, R3 is C1-10 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R3 is unsubstituted C1-10 alkyl. In certain embodiments, R3 is C1-10 alkyl, substituted with one or more substituents Q. In certain embodiments, R3 is C1-10 alkyl, substituted with one or more halo. In certain embodiments, R3 is C1-10 alkyl, substituted with one or more fluoro. In certain embodiments, R3 is C1-10 alkyl, substituted with one, two, or three fluoro.
In certain embodiments, R3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3 is butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, each optionally substituted with one or more substituents Q.
In certain embodiments, R3 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each optionally substituted with one or more substituents Q. In certain embodiments, R3 is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each optionally substituted with one or more substituents Q.
In certain embodiments, R3 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each of which is unsubstituted. In certain embodiments, R3 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each of which is unsubstituted. In certain embodiments, R3 is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each of which is unsubstituted.
In certain embodiments, R3 is trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluorotetradecyl, trifluoro-pentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluorooctadecyl, trifluorononadecyl, or trifluoroeicosyl. In certain embodiments, R3 is trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, or trifluorodecyl. In certain embodiments, R3 is trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, or trifluorodecyl.
In certain embodiments, R3 is trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-prop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13-trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16-trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19-trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl. In certain embodiments, R3 is trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, or 10,10,10-trifluorodec-1-yl. In certain embodiments, R3 is 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, or 10,10,10-trifluorodec-1-yl.
In certain embodiments, R3 is C1-20 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R3 is 2-(2-(pentyloxy)ethoxy)ethyl or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl. In certain embodiments, R3 is C2-20 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R3 is C2-20 alkynyl, optionally substituted with one or more substituents Q.
In certain embodiments, R3 is hexyl, octyl, decyl, trifluorohexyl, trifluorooctyl, or trifluorodecyl. In certain embodiments, R3 is n-hexyl, n-octyl, n-decyl, 6,6,6-trifluorohex-1-yl, 8,8,8-trifluorooct-1-yl, or 10,10,10-trifluorodec-1-yl. In certain embodiments, R3 is n-hexyl, n-octyl, 6,6,6-trifluorohex-1-yl, or 8,8,8-trifluorooct-1-yl. In certain embodiments, R3 is n-hexyl, n-octyl, n-decyl, 6,6,6-trifluorohex-1-yl, 8,8,8-trifluorooct-1-yl, 10,10,10-trifluorodec-1-yl, 2-(2-(pentyloxy)ethoxy)ethyl, or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl. In certain embodiments, R3 is n-hexyl, n-octyl, 6,6,6-trifluorohex-1-yl, 8,8,8-trifluorooct-1-yl, 2-(2-(pentyloxy)ethoxy)-ethyl, or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl.
In certain embodiments, R4 is C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4 is unsubstituted C1-20 alkyl. In certain embodiments, R4 is C1-20 alkyl, substituted with one or more substituents Q. In certain embodiments, R4 is C1-20 alkyl, substituted with one or more halo. In certain embodiments, R4 is C1-20 alkyl, substituted with one or more fluoro. In certain embodiments, R4 is C1-20 alkyl, substituted with one, two, or three fluoro.
In certain embodiments, R4 is C1-10 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4 is unsubstituted C1-10 alkyl. In certain embodiments, R4 is C1-10 alkyl, substituted with one or more substituents Q. In certain embodiments, R4 is C1-10 alkyl, substituted with one or more halo. In certain embodiments, R4 is C1-10 alkyl, substituted with one or more fluoro. In certain embodiments, R4 is C1-10 alkyl, substituted with one, two, or three fluoro.
In certain embodiments, R4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4 is butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl, each optionally substituted with one or more substituents Q.
In certain embodiments, R4 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each optionally substituted with one or more substituents Q. In certain embodiments, R4 is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each optionally substituted with one or more substituents Q.
In certain embodiments, R4 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, or n-eicosyl, each of which is unsubstituted. In certain embodiments, R4 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each of which is unsubstituted. In certain embodiments, R4 is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, each of which is unsubstituted.
In certain embodiments, R4 is trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, trifluorodecyl, trifluoroundecyl, trifluorododecyl, trifluorotridecyl, trifluorotetradecyl, trifluoro-pentadecyl, trifluorohexadecyl, trifluoroheptadecyl, trifluorooctadecyl, trifluorononadecyl, or trifluoroeicosyl. In certain embodiments, R4 is trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, or trifluorodecyl. In certain embodiments, R4 is trifluorobutyl, trifluoropentyl, trifluorohexyl, trifluoroheptyl, trifluorooctyl, trifluorononyl, or trifluorodecyl.
In certain embodiments, R4 is trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-prop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, 10,10,10-trifluorodec-1-yl, 11,11,11-trifluoroundec-1-yl, 12,12,12-trifluorododec-1-yl, 13,13,13-trifluorotridec-1-yl, 14,14,14-trifluorotetradec-1-yl, 15,15,15-trifluoropentadec-1-yl, 16,16,16-trifluorohexadec-1-yl, 17,17,17-trifluoroheptadec-1-yl, 18,18,18-trifluorooctadec-1-yl, 19,19,19-trifluorononadec-1-yl, or 20,20,20-trifluoroeicosyl. In certain embodiments, R4 is trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl, 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, or 10,10,10-trifluorodec-1-yl. In certain embodiments, R4 is 4,4,4-trifluorobut-1-yl, 5,5,5-trifluoropent-1-yl, 6,6,6-trifluorohex-1-yl, 7,7,7-trifluorohept-1-yl, 8,8,8-trifluorooct-1-yl, 9,9,9-trifluoronon-1-yl, or 10,10,10-trifluorodec-1-yl.
In certain embodiments, R4 is C1-20 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R4 is 2-(2-(pentyloxy)ethoxy)ethyl or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl. In certain embodiments, R4 is C2-20 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R4 is C2-20 alkynyl, optionally substituted with one or more substituents Q.
In certain embodiments, R4 is hexyl, octyl, decyl, trifluorohexyl, trifluorooctyl, or trifluorodecyl. In certain embodiments, R4 is n-hexyl, n-octyl, n-decyl, 6,6,6-trifluorohex-1-yl, 8,8,8-trifluorooct-1-yl, or 10,10,10-trifluorodec-1-yl. In certain embodiments, R4 is n-octyl or 8,8,8-trifluorooct-1-yl. In certain embodiments, R4 is n-hexyl, n-octyl, n-decyl, 6,6,6-trifluoro-hex-1-yl, 8,8,8-trifluorooct-1-yl, 10,10,10-trifluorodec-1-yl, 2-(2-(pentyloxy)ethoxy)ethyl, or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl. In certain embodiments, R4 is n-octyl, 8,8,8-trifluoro-oct-1-yl, 2-(2-(pentyloxy)ethoxy)ethyl, or 2-(2-(2-(undecyloxy)ethoxy)ethoxy)ethyl.
In certain embodiments, R5 is —C(O)OR5a, wherein R5a is as defined herein. In certain embodiments, R5 is —C(O)OH. In certain embodiments, R5 is —C(O)O—C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R5 is —C(O)OCH3. In certain embodiments, R5 is —OR5a, wherein R5a is as defined herein. In certain embodiments, R5 is hydroxyl. In certain embodiments, R5 is C1-6 alkoxy, optionally substituted with one or more substituents Q. In certain embodiments, R5 is methoxy. In certain embodiments, R5 is —OC(O)R5a, wherein R5a is as defined herein. In certain embodiments, R5 is —OC(O)—C1-20 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R5 is formoxy or acetoxy.
In certain embodiments, R1a is hydrogen. In certain embodiments, R1a is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R1a is C1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R1a is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R1a is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R1a is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R1a is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R1a is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R1a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R1a is heterocyclyl, optionally substituted with one or more substituents Q.
In certain embodiments, R2a is hydrogen. In certain embodiments, R2a is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2a is C1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2a is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R2a is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R2a is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2a is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R2a is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R2a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R2a is heterocyclyl, optionally substituted with one or more substituents Q.
In certain embodiments, L1 is C1-20 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L1 is unsubstituted C1-20 alkylene. In certain embodiments, L1 is C1-20 alkylene, substituted with one or more substituents Q. In certain embodiments, L1 is C1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L1 is unsubstituted C1-10 alkylene. In certain embodiments, L1 is C1-10 alkylene, substituted with one or more substituents Q.
In certain embodiments, L1 is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, tetradecanediyl, pentadecanediyl, hexadecanediyl, heptadecanediyl, octadecanediyl, nonadecanediyl, or eicosanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L1 is ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, or decanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L1 is butanediyl, pentanediyl, hexanediyl, heptanediyl, or octanediyl, each optionally substituted with one or more substituents Q.
In certain embodiments, L1 is methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane-1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18-diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L1 is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L1 is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl, each optionally substituted with one or more substituents Q.
In certain embodiments, L1 is methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane-1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18-diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each of which is unsubstituted. In certain embodiments, L1 is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each of which is unsubstituted. In certain embodiments, L1 is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl, each of which is unsubstituted.
In certain embodiments, L1 is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L1 is —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, —(CH2)3O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L1 is —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)3O(CH2)3—. In certain embodiments, L1 is —(CH2)2O(CH2)2—. In certain embodiments, L1 is —(CH2)2O(CH2)3—. In certain embodiments, L1 is —(CH2)3O(CH2)3—. In certain embodiments, L1 is —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L1 is —N(H)—C1-20 alkenylene or —N(H)—C1-20 heteroalkenylene, each optionally substituted with one or more substituents Q. In certain embodiments, L1 is —N(H)—C1-20 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L1 is —N(H)—C1-10 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L1 is —N(H)(CH2)2—, —N(H)(CH2)3—, —N(H)(CH2)4—, —N(H)(CH2)5—, —N(H)(CH2)6—, —N(H)(CH2)7—, or —N(H)(CH2)8—, each optionally substituted with one or more substituents Q. In certain embodiments, L1 is —N(H)—C1-20 heteroalkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L1 is C2-20 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L1 is C2-20 alkynylene, optionally substituted with one or more substituents Q.
In certain embodiments, L1 is pentanediyl, hexanediyl, heptanediyl, —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L1 is pentanediyl, hexanediyl, heptanediyl, or —(CH2)2O(CH2)3—. In certain embodiments, L1 is pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L1 is pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or —(CH2)2O(CH2)3—. In certain embodiments, L1 is pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, —(CH2)2O(CH2)2O(CH2)2—, or —N(H)(CH2)6—.
In certain embodiments, L2 is C1-20 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2 is unsubstituted C1-20 alkylene. In certain embodiments, L2 is C1-20 alkylene, substituted with one or more substituents Q.
In certain embodiments, L2 is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, tetradecanediyl, pentadecanediyl, hexadecanediyl, heptadecanediyl, octadecanediyl, nonadecanediyl, or eicosanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2 is ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, or decanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2 is butanediyl, pentanediyl, hexanediyl, heptanediyl, or octanediyl, each optionally substituted with one or more substituents Q.
In certain embodiments, L2 is methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane-1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18-diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2 is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2 is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl, each optionally substituted with one or more substituents Q.
In certain embodiments, L2 is methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane-1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18-diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each of which is unsubstituted. In certain embodiments, L2 is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each of which is unsubstituted. In certain embodiments, L2 is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl, each of which is unsubstituted.
In certain embodiments, L2 is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2 is —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, —(CH2)3O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L2 is —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)3O(CH2)3—. In certain embodiments, L2 is —(CH2)2O(CH2)2—. In certain embodiments, L2 is —(CH2)2O(CH2)3—. In certain embodiments, L2 is —(CH2)3O(CH2)3—. In certain embodiments, L2 is —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L2 is —N(H)—C1-20 alkenylene or —N(H)—C1-20 heteroalkenylene, each optionally substituted with one or more substituents Q. In certain embodiments, L2 is —N(H)—C1-20 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L2 is —N(H)—C1-10 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L2 is —N(H)(CH2)2—, —N(H)(CH2)3—, —N(H)(CH2)4—, —N(H)(CH2)5—, —N(H)(CH2)6—, —N(H)(CH2)7—, or —N(H)(CH2)8—, each optionally substituted with one or more substituents Q. In certain embodiments, L2 is —N(H)—C1-20 heteroalkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L2 is C2-20 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L2 is C2-20 alkynylene, optionally substituted with one or more substituents Q.
In certain embodiments, L2 is pentanediyl, hexanediyl, heptanediyl, —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L2 is pentanediyl, hexanediyl, heptanediyl, or —(CH2)2O(CH2)3—. In certain embodiments, L2 is pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L2 is pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or —(CH2)2O(CH2)3—. In certain embodiments, L2 is pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, —(CH2)2O(CH2)2O(CH2)2—, or —N(H)(CH2)6—.
In certain embodiments, L3 is C1-20 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L3 is unsubstituted C1-20 alkylene. In certain embodiments, L3 is C1-20 alkylene, substituted with one or more substituents Q.
In certain embodiments, L3 is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, tetradecanediyl, pentadecanediyl, hexadecanediyl, heptadecanediyl, octadecanediyl, nonadecanediyl, or eicosanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L3 is ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, or decanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L3 is ethanediyl, propanediyl, butanediyl, pentanediyl, or hexanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L3 is ethanediyl, propanediyl, butanediyl, or pentanediyl, each optionally substituted with one or more substituents Q.
In certain embodiments, L3 is methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane-1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18-diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L3 is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L3 is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, or hexane-1,6-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L3 is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, or pentane-1,5-diyl, each optionally substituted with one or more substituents Q.
In certain embodiments, L3 is methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane-1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18-diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each of which is unsubstituted. In certain embodiments, L3 is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each of which is unsubstituted. In certain embodiments, L3 is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, or hexane-1,6-diyl, each of which is unsubstituted. In certain embodiments, L3 is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, or pentane-1,5-diyl, each of which is unsubstituted.
In certain embodiments, L3 is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L3 is —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)3O(CH2)3—. In certain embodiments, L3 is —(CH2)2O(CH2)2—. In certain embodiments, L3 is —(CH2)2O(CH2)3—. In certain embodiments, L3 is —(CH2)3O(CH2)3—. In certain embodiments, L3 is C2-20 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L3 is C2-20 alkynylene, optionally substituted with one or more substituents Q.
In certain embodiments, L3 is ethanediyl or butanediyl. In certain embodiments, L3 is ethane-1,2-diyl or butane-1,4-diyl.
In certain embodiments, L1a is C1-20 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L1a is unsubstituted C1-20 alkylene. In certain embodiments, L1a is C1-20 alkylene, substituted with one or more substituents Q. In certain embodiments, L1a is C1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L1a is unsubstituted C1-10 alkylene. In certain embodiments, L1a is C1-10 alkylene, substituted with one or more substituents Q.
In certain embodiments, L1a is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, tetradecanediyl, pentadecanediyl, hexadecanediyl, heptadecanediyl, octadecanediyl, nonadecanediyl, or eicosanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L1a is ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, or decanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L1a is butanediyl, pentanediyl, hexanediyl, heptanediyl, or octanediyl, each optionally substituted with one or more substituents Q.
In certain embodiments, L1a is methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane-1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18-diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L1a is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L1a is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl, each optionally substituted with one or more substituents Q.
In certain embodiments, L1a is methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane-1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18-diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each of which is unsubstituted. In certain embodiments, L1a is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each of which is unsubstituted. In certain embodiments, L1a is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl, each of which is unsubstituted.
In certain embodiments, L1a is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L1a is —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, —(CH2)3O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L1a is —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)3O(CH2)3—. In certain embodiments, L1a is —(CH2)2O(CH2)2—. In certain embodiments, L1a is —(CH2)2O(CH2)3—. In certain embodiments, L1a is —(CH2)3O(CH2)3—. In certain embodiments, L1a is —(CH2)2O(CH2)2O(CH2)2—.
In certain embodiments, L1a is pentanediyl, hexanediyl, heptanediyl, —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L1a is pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—.
In certain embodiments, L2a is C1-20 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2a is unsubstituted C1-20 alkylene. In certain embodiments, L2a is C1-20 alkylene, substituted with one or more substituents Q. In certain embodiments, L2a is C1-10 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2a is unsubstituted C1-10 alkylene. In certain embodiments, L2a is C1-10 alkylene, substituted with one or more substituents Q.
In certain embodiments, L2a is methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, tetradecanediyl, pentadecanediyl, hexadecanediyl, heptadecanediyl, octadecanediyl, nonadecanediyl, or eicosanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2a is ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, or decanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2a is butanediyl, pentanediyl, hexanediyl, heptanediyl, or octanediyl, each optionally substituted with one or more substituents Q.
In certain embodiments, L2a is methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane-1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18-diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2a is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L2a is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl, each optionally substituted with one or more substituents Q.
In certain embodiments, L2a is methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, tetradecane-1,14-diyl, pentadecane-1,15-diyl, hexadecane-1,16-diyl, heptadecane-1,17-diyl, octadecane-1,18-diyl, nonadecane-1,19-diyl, or eicosane-1,20-diyl, each of which is unsubstituted. In certain embodiments, L2a is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl, each of which is unsubstituted. In certain embodiments, L2a is butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl, each of which is unsubstituted.
In certain embodiments, L2a is C1-20 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L2a is —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, —(CH2)3O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L2a is —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)3O(CH2)3—. In certain embodiments, L2a is —(CH2)2O(CH2)2—. In certain embodiments, L2a is —(CH2)2O(CH2)3—. In certain embodiments, L2a is —(CH2)3O(CH2)3—. In certain embodiments, L2a is —(CH2)2O(CH2)2O(CH2)2—.
In certain embodiments, L2a is pentanediyl, hexanediyl, heptanediyl, —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—. In certain embodiments, L2a is pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, —(CH2)2O(CH2)2—, —(CH2)2O(CH2)3—, or —(CH2)2O(CH2)2O(CH2)2—.
In certain embodiments, U is —C(O)—. In certain embodiments, U is —C(O)O—. In certain embodiments, U is —OC(O)O—.
In certain embodiments, V is —C(O)—. In certain embodiments, V is —C(O)O—. In certain embodiments, V is —OC(O)O—.
In certain embodiments, X is C(H). In certain embodiments, X is N.
In certain embodiments, Y is C(H). In certain embodiments, Y is N.
In one embodiment, provided herein is a compound of:
In another embodiment, provided herein is a compound of:
In certain embodiments, a compound provided herein is deuterium-enriched. In certain embodiments, a compound provided herein is carbon-13 enriched. In certain embodiments, a compound provided herein is carbon-14 enriched. In certain embodiments, a compound provided herein contains one or more less prevalent isotopes for other elements, including, but not limited to, 15N for nitrogen; 17O or 18O for oxygen, and 34S, 35S, or 36S for sulfur.
In certain embodiments, a compound provided herein has an isotopic enrichment factor of no less than about 5, no less than about 10, no less than about 20, no less than about 50, no less than about 100, no less than about 200, no less than about 500, no less than about 1,000, no less than about 2,000, no less than about 5,000, or no less than about 10,000. In any events, however, an isotopic enrichment factor for a specified isotope is no greater than the maximum isotopic enrichment factor for the specified isotope, which is the isotopic enrichment factor when a compound at a given position is 100% enriched with the specified isotope. Thus, the maximum isotopic enrichment factor is different for different isotopes. The maximum isotopic enrichment factor is 6,410 for deuterium and 90 for carbon-13.
In certain embodiments, a compound provided herein has a deuterium enrichment factor of no less than about 64 (about 1% deuterium enrichment), no less than about 130 (about 2% deuterium enrichment), no less than about 320 (about 5% deuterium enrichment), no less than about 640 (about 10% deuterium enrichment), no less than about 1,300 (about 20% deuterium enrichment), no less than about 3,200 (about 50% deuterium enrichment), no less than about 4,800 (about 75% deuterium enrichment), no less than about 5,130 (about 80% deuterium enrichment), no less than about 5,450 (about 85% deuterium enrichment), no less than about 5,770 (about 90% deuterium enrichment), no less than about 6,090 (about 95% deuterium enrichment), no less than about 6,220 (about 97% deuterium enrichment), no less than about 6,280 (about 98% deuterium enrichment), no less than about 6,350 (about 99% deuterium enrichment), or no less than about 6,380 (about 99.5% deuterium enrichment). The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy. In certain embodiments, at least one of the atoms of a compound provided herein, as specified as deuterium-enriched, has deuterium enrichment of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
In certain embodiments, a compound provided herein is isolated or purified. In certain embodiments, a compound provided herein has a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.
The compounds provided herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified. Where a compound provided herein contains an alkenyl group, the compound may exist as one or mixture of geometric cis/trans (or Z/E) isomers. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contains an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
A compound provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of ordinary skill in the art will recognize that administration of a compound in its (R) form is equivalent, for the compound that undergoes epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.
When a compound provided herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a solvate. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a hydrate.
Suitable acids for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, ca-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid, (L)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.
Suitable bases for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethyl-amino)ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.
The disclosure will be further understood by the following non-limiting examples.
As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar); mmol (millimoles); min (minute or minutes); h (hour or hours); Bn (benzyl); Boc (tert-butoxycarbonyl); DCM (dichloromethane); DMF (dimethylformamide); DMAP (4-dimethylaminopyridine); EDCI (1-ethyl-3-(3-dimethylamino-propyl)carbodiimide); TEA (triethylamine); TFA (trifluoroacetic acid); LCMS (liquid chromatography-mass spectrometry); MS (mass spectrometry); NMR (nuclear magnetic resonance); and prep-HPLC (preparative high performance liquid chromatography).
For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). All reactions are conducted at room temperature unless otherwise specified. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.
Compound A1 was prepared as shown in Scheme 1.
N-Hexyloctan-1-amine 1.2. A solution of 1-octanamine 1.1 (30 mL, 181 mmol) and hexanal (26.5 mL, 217 mmol) in dry ethanol (400 mL) was stirred for 6 h at room temperature, followed by addition of NaBH4 (13.7 g, 362 mmol) at 0° C. After stirred at room temperature overnight, the reaction mixture was concentrated in vacuo and then treated with NaOH (4N, 600 mL). The mixture was stirred for 20-30 min and extracted with diethyl ether (3×200 mL). The combined organic phase was washed with water (2×100 mL) and brine (1×100 mL), dried over anhydrous MgSO4, and concentrated in vacuo to afford compound 1.2 (39 g) in 95% yield.
8-Bromo-N-hexyl-N-octyloctanamide 1.3. To a solution of 8-bromooctanoic acid (2.2 g, 9.65 mmol) and DMAP (9 mg, 0.074 mmol) in dry DCM was added EDCI (2.9 g, 15 mmol). After the solution was stirred for 20-30 min at room temperature, compound 1.2 (1.6 g, 7.42 mmol) was added. The reaction mixture was stirred at room temperature overnight, and then diluted in DCM (150 mL), washed with water (3×50 mL), and concentrated in vacuo to yield a crude product, which was purified by silica gel column chromatography eluting with MeOH in DCM (0-10%) to afford compound 1.3 (2.6 g) in 84% yield.
N-Hexyl-8-((2-hydroxyethyl)amino)-N-octyloctanamide 1.4. A solution of compound 1.3 (0.61 g, 1.46 mmol) and ethanolamine (4.4 mL. 73 mmol) in dry DCM (3 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with DCM (50 mL), washed with water (3×15 mL), dried over anhydrous MgSO4, and concentrated in vacuo to afford compound 1.4 (0.53 g) in 91% yield.
8,8′-((2-Hydroxyethyl)azanediyl)bis(N-hexyl-N-octyloctanamide) A1. A mixture of compound 1.3 (0.84 g, 2 mmol), compound 1.4 (0.53 g, 1.33 mmol), K2CO3 (0.37 g, 2.66 mmol), and KI (a catalytic amount) in dry DMF (5 mL) was stirred at 70° C. overnight. The reaction mixture was then diluted with DCM (50 mL), washed with water (3×15 mL), dried over anhydrous MgSO4, and concentrated in vacuo to yield a crude product, which was purified by silica gel column chromatography eluting with MeOH in DCM (0-10%) to afford compound A1 (0.64 g) in 66% yield. 1H NMR (300 MHz, CDCl3) δ 3.67 (s, 2H), 3.23 (dt, J=25.7, 7.5 Hz, 8H), 2.70 (d, J=38.1 Hz, 6H), 2.27 (t, J=7.5 Hz, 4H), 1.74-1.40 (m, 16H), 1.29 (dd, J=12.9, 7.1 Hz, 44H), 0.88 (h, J=3.4 Hz, 12H).
Compound A2 is prepared as shown in Scheme 2.
6-Bromohexyl (4-nitrophenyl)carbonate 2.2. To a solution of 6-bromo-1-hexanol 2.1 (2.77 g, 15.3 mmol) and pyridine (2.3 mL, 29 mmol) in dry DCM (10 mL) was added nitrophenyl chloroformate (6.2 g, 31 mmol) at 0° C. After stirred at room temperature overnight, the reaction mixture was diluted with DCM (100 mL) and washed with water (3×30 mL). The combined organic phase was filtered through silica and the concentrated to afford compound 2.2, which was used directly in the next step without further purification.
6-Bromohexyl hexyl(octyl)carbamate 2.3. A solution of compound 1.2 (0.78 g, 3.7 mmol) and compound 2.2 (1.32 g, 3.8 mmol) in dry DMF (10 mL) was stirred at 50° C. The reaction mixture was concentrated and then filtered through silica to yield compound 2.3, which was used directly in the next step without further purification.
6-((2-Hydroxyethyl)amino)hexyl hexyl(octyl)carbamate 2.4. A solution of compound 2.3 (2.63 g, 12.3 mmol) and ethanolamine (337 mL, 61.6 mmol) in dry DCM (10 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with DCM (50 mL) and washed with water (3×20 mL). The organic phase was concentrated to yield a crude product, which was purified by silica gel column chromatography eluting with MeOH in DCM to afford compound 2.4 (0.64 g). 1H NMR (300 MHz, CDCl3) δ 4.05 (t, J=6.6 Hz, 2H), 3.72 (t, J=5.1 Hz, 2H), 3.17 (s, 4H), 2.86 (t, J=5.1 Hz, 2H), 2.71 (t, J=7.3 Hz, 2H), 2.37 (s, 2H), 1.73-1.16 (m, 28H), 1.01-0.71 (m, 6H).
((2-Hydroxyethyl)azanediyl)bis(hexane-6,1-diyl) bis(hexyl(octyl)carbamate) A2. Compound A2 is prepared from compound 2.4 according to the procedures described in Example 1 for compound A1.
Compound A3 is prepared as shown in Scheme 3.
Compound A4 was prepared as shown in Scheme 4.
((Azanediylbis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-hexyl-decanoate) 4.3. To a solution of compound 4.2 (2.3 g, 8.82 mmol), DMAP (0.22 g, 1.77 mmol), and TEA (2.5 mL, 18 mmol) in dry DCM (20 mL) was added EDCI (2 g, 11 mmol). The mixture was stirred for 30 min at room temperature. Compound 4.1 (1 g, 3.53 mmol) was then added. After stirred at room temperature overnight, the reaction mixture was washed with 1N HCl, water, dried over anhydrous MgSO4, and concentrated to yield protected compound 4.3, which was deprotected with H2 in the presence of Pd/C (500 mg) in ethanol (150 mL) overnight. The reaction mixture was filtered through celite and concentrated to afford compound 4.3 (2.67 g), which was used directly in the next step without further purification.
((((2-Hydroxyethyl)azanediyl)bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-hexyldecanoate) A4. A mixture of compound 4.3 (0.65 g, 0.97 mmol), 2-bromoethanol (6.1 g, 49 mmol), KI (a catalytic amount), and K2CO3 (0.54 g, 3.88 mmol) in dry DMF (3 mL) was stirred at 70° C. overnight. The reaction mixture was concentrated, diluted with water, and extracted with DCM. The combined organic phase was concentrated to yield a crude product, which was purified by silica gel column chromatography eluting with MeOH in DCM to afford compound A4 (0.56 g) in 81% yield. 1H NMR (300 MHz, CDCl3) δ 4.22 (d, J=5.1 Hz, 4H), 3.88-3.44 (m, 16H), 2.42-2.25 (m, 2H), 1.57-1.25 (s, 48H), 0.97-0.82 (m, 12H).
Compound A5 was prepared as shown in Scheme 5.
Di(heptadecan-9-yl) 4,7,13,16-tetraoxa-10-azanonadecanedioate 5.3. To a mixture of compound 5.1 (0.5 g, 1.14 mmol), DMAP (35 mg, 0.29 mmol), and TEA (0.48 mL, 3.43 mmol) in dry DCM (10 mL) was added EDCI (0.33 g, 1.71 mmol). After the solution was stirred for 30 min at room temperature, compound 5.2 (0.73 g, 2.86 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then washed with 1N HCl, water, dried over anhydrous MgSO4, and concentrated to yield a crude protected compound, which was purified by silica gel column chromatography eluting with using MeOH in DCM to afford a protected compound 5.3 (0.84 g) in 81% yield. The protected compound was deprotected with TFA (10 mL) in DCM (10 mL) overnight. The reaction mixture was washed with H2O, dried over anhydrous MgSO4, and concentrated to afford compound 5.3 (0.81 g), which was used directly in the next step without further purification.
Di(heptadecan-9-yl) 10-(2-hydroxyethyl)-4,7,13,16-tetraoxa-10-azanonadecane-dioate A5. A mixture of compound 5.3 (0.81 g, 0.1 mmol), 2-bromoethanol (2.49 g, 20 mmol), KI (a catalytic amount), and K2CO3 (0.55 g, 3.98 mmol) in dry DMF (5 mL) was stirred at 70° C. The reaction mixture was concentrated, diluted with water, and extracted with DCM. The organic phase was concentrated to yield a crude product, which was purified by silica gel column chromatography eluting with MeOH in DCM to afford compound A5 (0.41 g) in 75% yield. 1H NMR (300 MHz, CDCl3) δ 4.87 (t, J=6.2 Hz, 2H), 3.73 (t, J=6.6 Hz, 8H), 3.60 (s, 8H), 3.10 (s, 6H), 2.57 (t, J=6.5 Hz, 4H), 1.50 (d, J=6.8 Hz, 8H), 1.25 (s, 48H), 0.97-0.80 (m, 12H).
Compound A6 is prepared as shown in Scheme 6.
Compound A7 is prepared as shown in Scheme 7.
Compound A10 was prepared as shown in Scheme 8.
11,11,11-Trifluoroundecan-1-ol 8.2. To a mixture of NaSO2CF3 (2 g, 12.8 mmol) and Mn(OAc)3·H2O (6.9 g, 26 mmol) under Ar was added compound 8.1 (2 g, 12.8 mmol), followed by addition of acetic acid (150 mL). After stirred for 24 h at room temperature, the reaction mixture was poured into a solution containing Na2S2O4 (15 g) in water (800 mL). Na2CO3 was then added slowly until bubbles stopped forming (pH ˜7). The reaction mixture was extracted with DCM, washed with H2O, dried over anhydrous MgSO4, and concentrated to afford compound 8.2, which was used directly in the next reaction without further purification.
11,11,11-Trifluoroundecyl 6-bromohexanoate 8.3. To a solution of 6-bromo-hexanoic acid (0.62 g, 3.18 mmol), DMAP (65 mg, 0.63 mmol), and TEA (0.74 mL, 5.30 mmol) in dry DCM (15 mL) was added EDCI (0.71 g, 3.71 mmol). The mixture was stirred for 30 min at room temperature and compound 8.2 (0.6 g, 2.65 mmol). After stirred at room temperature overnight, the reaction mixture was washed with 1N HCl, water, dried over anhydrous MgSO4, and concentrated to afford compound 8.3, which was used directly in the next reaction without further purification.
Heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)-hexyl)amino)octanoate A10. A mixture of compound 8.3 (0.52 g, 1.29 mmol), compound 8.4 (0.47 g, 1.07 mmol), KI (a catalytic amount), and K2CO3 (0.22 g, 1.61 mmol) in dry DMF (3 mL) was stirred overnight at 70° C. After concentrated, the reaction mixture was diluted with water and extracted with DCM. The organic phase was concentrated to yield a crude product, which was purified by silica gel column chromatography eluting with MeOH in DCM to afford compound A10 (0.3 g) in 37% yield. 1H NMR (300 MHz, CDCl3) δ 4.84 (p, J=6.3 Hz, 1H), 4.04 (t, J=6.8 Hz, 2H), 3.84 (t, J=4.9 Hz, 2H), 2.98 (t, J=5.0 Hz, 2H), 2.86 (dt, J=8.5, 4.3 Hz, 4H), 2.28 (dt, J=12.1, 7.4 Hz, 4H), 2.03 (dd, J=9.2, 6.7 Hz, 2H), 1.85-1.10 (m, 62H), 0.97-0.71 (m, 6H); 19F NMR (282 MHz, CDCl3) δ −66.39.
The following compounds were prepared similarly according to the synthetic procedures or methodologies exemplified herein.
Heptadecan-9-yl (6-((3-hydroxypropyl)(6-(((undecyloxy)carbonyl)amino)hexyl)-amino)hexyl)carbamate A46. 1H NMR (300 MHz, CDCl3) δ 4.84 (m, 1H), 4.72 (m, 2H), 4.01 (t, J=6.80 Hz, 2H), 3.77 (t, J=6.80 Hz, 2H), 3.15 (m, 6H), 2.67 (t, J=6.72 Hz, 2H), 2.44 (m, 4H), 1.62-1.33 (m, 12H), 1.32-1.18 (m, 50H), 0.86 (t, J=6.74 Hz, 9H); MS (ESI) m z: 754.1 [M+H]+.
N,N-(((4-Hydroxybutyl)azanediyl)bis(hexane-6,1-diyl))bis(2-hexyldecanamide) A48. 1H NMR (300 MHz, CDCl3) δ 5.69 (t, J=4.89 Hz, 2H), 3.55 (m, 2H), 3.23 (m, 4H), 2.46 (m, 6H), 1.51 (m, 2H), 1.62-1.40 (m, 12H), 1.39-1.16 (m, 58H), 0.87 (t, J=6.83 Hz, 12H).
N,N-(((2-Hydroxyethyl)azanediyl)bis(hexane-6,1-diyl))bis(2-hexyldecanamide) A49. 1H NMR (300 MHz, CDCl3) δ 5.59 (t, J=4.98 Hz, 2H), 3.55 (m, 2H), 3.25 (m, 4H), 2.60 (m, 2H), 2.44 (m, 4H), 1.89 (m, 2H), 1.70-1.38 (m, 14H), 1.38-1.16 (m, 40H), 0.87 (t, J=6.88 Hz 12H).
Heptadecan-9-yl 6-((2-hydroxyethyl)(5-(nonyloxy)-5-oxopentyl)amino)hexanoate B1. 1H NMR (300 MHz, CDCl3) b 4.86 (m, 1H), 4.06 (t, J=6.81 Hz, 2H), 3.58 (m, 2H), 2.65 (m, 2H), 2.53 (m, 4H), 2.29 (m, 4H), 1.79-1.40 (m, 18H), 1.39-1.12 (m, 36H), 0.88 (t, J=6.80 Hz, 9H).
Heptadecan-9-yl 6-((6-(heptyloxy)-6-oxohexyl)(2-hydroxyethyl)amino)hexanoate B2. 1H NMR (300 MHz, CDCl3) δ 4.83 (m, 1H), 4.08 (t, J=6.72 Hz, 2H), 2.98-2.43 (m, 6H), 2.33 (m, 4H), 1.74-1.50 (m, 16H), 1.50-1.24 (m, 36H), 0.90 (t, J=6.81 Hz, 9H).
Heptadecan-9-yl 6-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)-hexanoate B3. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.74 Hz, 2H), 3.51 (t, J=6.68 Hz, 2H), 2.56 (t, J=6.70 Hz, 2H), 2.44 (t, J=6.78 Hz, 4H), 2.28 (m, 4H), 1.63 (m, 6H), 1.48 (m, 4H), 1.46-1.22 (m, 48H), 0.88 (t, J=6.82 Hz, 9H).
Heptadecan-9-yl 7-((7-(heptyloxy)-7-oxoheptyl)(2-hydroxyethyl)amino)-heptanoate B4. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.74 Hz, 2H), 3.51 (t, J=6.70 Hz, 2H), 2.55 (t, J=6.69 Hz, 2H), 2.42 (m, 4H), 2.28 (m, 4H), 1.64 (m, 6H), 1.49 (m, 6H), 1.46-1.22 (m, 42H), 0.86 (t, J=6.80 Hz, 9H).
Heptadecan-9-yl 7-((2-hydroxyethyl)(7-(nonyloxy)-7-oxoheptyl)amino)-heptanoate B5. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.76 Hz, 2H), 3.51 (t, J=6.71 Hz, 2H), 2.56 (t, J=6.69 Hz, 2H), 2.43 (m, 4H), 2.28 (m, 4H), 1.62 (m, 6H), 1.48 (m, 6H), 1.46-1.19 (m, 44H), 0.87 (t, J=6.82 Hz, 9H).
Heptadecan-9-yl 7-((2-hydroxyethyl)(7-oxo-7-(undecyloxy)heptyl)amino)-heptanoate B6. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.76 Hz, 2H), 3.59 (t, J=4.96 Hz, 2H), 2.66 (t, J=4.98 Hz, 2H), 2.53 (m, 4H), 2.29 (m, 4H), 1.70-1.49 (m, 14H), 1.48-1.17 (m, 46H), 0.87 (t, J=6.82 Hz, 9H).
Heptadecan-9-yl 8-((8-(heptyloxy)-8-oxooctyl)(2-hydroxyethyl)amino)octanoate B7. 1H NMR (300 MHz, CDCl3) δ 4.84 (m, 1H), 4.03 (t, J=6.84 Hz, 2H), 3.51 (t, J=5.98 Hz, 2H), 2.57 (t, J=5.98 Hz, 2H), 2.44 (m, 4H), 2.28 (m, 4H), 1.67-1.40 (m, 12H), 1.38-1.17 (m, 44H), 0.85 (t, J=6.80 Hz, 9H).
Heptadecan-9-yl 8-((2-hydroxyethyl)(8-oxo-8-(undecyloxy)octyl)amino)-octanoate B8. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.80 Hz, 2H), 3.63 (m, 2H), 2.75-2.29 (m, 6H), 2.28 (m, 4H), 1.68-1.40 (m, 16H), 1.38-1.17 (m, 50H), 0.88 (t, J=6.78 Hz, 9H).
Heptadecan-9-yl 7-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)-heptanoate B9. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.80 Hz, 2H), 3.57 (m, 2H), 2.63 (m, 2H), 2.50 (m, 4H), 2.28 (m, 4H), 1.71-1.41 (m, 14H), 1.38-1.16 (m, 44H), 0.86 (t, J=6.80 Hz, 9H).
Heptadecan-9-yl 8-((6-(heptyloxy)-6-oxohexyl)(2-hydroxyethyl)amino)octanoate B10. 1H NMR (300 MHz, CDCl3) δ 4.88 (m, 1H), 4.05 (t, J=6.81 Hz, 2H), 3.67 (m, 2H), 2.75 (m, 2H), 2.62 (m, 4H), 2.30 (m, 4H), 1.75-1.46 (m, 12H), 1.43-1.13 (m, 40H), 0.88 (t, J=6.80 Hz, 9H).
Heptadecan-9-yl 8-((2-hydroxyethyl)(6-(nonyloxy)-6-oxohexyl)amino)octanoate B11. 1H NMR (300 MHz, CDCl3) δ 4.68 (m, 1H), 4.05 (t, J=6.81 Hz, 2H), 3.62 (m, 2H), 2.77-2.36 (m, 6H), 2.28 (m, 4H), 1.75-1.46 (m, 16H), 1.43-1.14 (m, 42H), 0.88 (t, J=6.81 Hz, 9H).
Heptyl 7-((6-(heptadecan-9-yloxy)-6-oxohexyl)(2-hydroxyethyl)amino)-heptanoate B12. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.84 Hz, 2H), 3.52 (t, J=5.98 Hz, 2H), 2.57 (t, J=6.00 Hz, 2H), 2.46 (m, 4H), 2.28 (m, 4H), 1.75-1.42 (m, 14H), 1.42-1.20 (m, 38H), 0.87 (t, J=6.80 Hz, 9H).
Undecyl 7-((6-(heptadecan-9-yloxy)-6-oxohexyl)(2-hydroxyethyl)amino)-heptanoate B13. 1H NMR (300 MHz, CDCl3) δ 4.88 (m, 1H), 4.07 (t, J=6.80 Hz, 2H), 3.55 (t, J=6.04 Hz, 2H), 2.58 (t, J=6.00 Hz, 2H), 2.48 (m, 4H), 2.30 (m, 4H), 1.64 (m, 6H), 1.51 (m, 8H), 1.45-1.20 (m, 46H), 0.89 (t, J=6.80 Hz, 9H).
Heptyl 8-((6-(heptadecan-9-yloxy)-6-oxohexyl)(2-hydroxyethyl)amino)octanoate B14. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.83 Hz, 2H), 3.51 (t, J=6.00 Hz, 2H), 2.56 (t, J=6.02 Hz, 2H), 2.45 (m, 4H), 2.28 (m, 4H), 1.63 (m, 6H), 1.49 (m, 4H), 1.45-1.20 (m, 44H), 0.86 (t, J=6.78 Hz, 9H).
Nonyl 8-((6-(heptadecan-9-yloxy)-6-oxohexyl)(2-hydroxyethyl)amino)octanoate B15. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.83 Hz, 2H), 3.61 (m, 2H), 2.68 (m, 2H), 2.55 (m, 4H), 2.29 (t, J=6.79 Hz, 4H), 1.72-1.46 (m, 12H), 1.45-1.20 (m, 44H), 0.87 (t, J=6.83 Hz, 9H).
Undecyl 8-((6-(heptadecan-9-yloxy)-6-oxohexyl)(2-hydroxyethyl)amino)-octanoate B16. 1H NMR (300 MHz, CDCl3) δ 4.85 (m, 1H), 4.04 (t, J=6.83 Hz, 2H), 3.91 (m, 2H), 3.15-2.80 (m, 6H), 2.29 (m, 4H), 1.74-1.46 (m, 16H), 1.45-1.20 (m, 46H), 0.87 (t, J=6.80 Hz, 9H).
Nonyl 8-((7-(heptadecan-9-yloxy)-7-oxoheptyl)(2-hydroxyethyl)amino)octanoate B17. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.81 Hz, 2H), 3.68 (m, 2H), 3.10-2.60 (m, 6H), 2.29 (m, 4H), 1.73-1.46 (m, 14H), 1.45-1.19 (m, 44H), 0.87 (t, J=6.80 Hz, 9H).
Heptadecan-9-yl 10-((2-hydroxyethyl)(8-(nonyloxy)-8-oxooctyl)amino)decanoate B18. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.79 Hz, 2H), 3.79 (m, 2H), 2.93-2.75 (m, 6H), 2.27 (m, 4H), 1.75-1.46 (m, 16H), 1.45-1.20 (m, 50H), 0.85 (t, J=6.82 Hz, 9H).
Heptadecan-9-yl 10-((2-hydroxyethyl)(10-oxo-10-(undecyloxy)decyl)amino)-decanoate B19. 1H NMR (300 MHz, CDCl3) δ 4.89 (m, 1H), 4.08 (t, J=6.84 Hz, 2H), 3.66 (m, 2H), 2.80-2.51 (m, 6H), 2.31 (m, 4H), 1.63 (m, 8H), 1.53 (m, 6H), 1.46-1.18 (m, 60H), 0.90 (t, J=6.79 Hz, 9H).
Heptadecan-9-yl 6-((6-(heptyloxy)-6-oxohexyl)(3-hydroxypropyl)amino)-hexanoate B20. 1H NMR (300 MHz, CDCl3) (4.90 (m, 1H), 4.05 (t, J=6.68 Hz, 2H), 3.78 (t, J=6.17 Hz, 2H), 2.63 (t, J=6.0 Hz, 2H), 2.41 (m, 4H), 2.31 (m, 4H), 1.72-1.53 (m, 9H), 1.51-1.43 (m, 4H), 1.32-1.14 (m, 40H), 0.87 (t, J=6.82 Hz, 9H).
Heptadecan-9-yl 6-((3-hydroxypropyl)(6-(nonyloxy)-6-oxohexyl)amino)-hexanoate B21. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.80 Hz, 2H), 3.81 (t, J=6.24 Hz, 2H), 2.86 (m, 2H), 2.67 (m, 4H), 2.31 (m, 4H), 1.79-1.46 (m, 20H), 1.45-1.18 (m, 36H), 0.87 (t, J=6.79 Hz, 9H).
Heptadecan-9-yl 7-((7-(heptyloxy)-7-oxoheptyl)(3-hydroxypropyl)amino)-heptanoate B22. 1H NMR (300 MHz, CDCl3) δ 4.85 (m, 1H), 4.05 (t, J=6.82 Hz, 2H), 3.82 (t, J=6.20 Hz, 2H), 3.09 (m, 2H), 2.90 (m, 4H), 2.28 (m, 4H), 1.92 (m, 2H), 1.78-1.12 (m, 54H), 0.86 (t, J=6.79 Hz, 9H).
Heptadecan-9-yl 8-((3-hydroxypropyl)(8-(nonyloxy)-8-oxooctyl)amino)octanoate B23. 1H NMR (300 MHz, CDCl3) δ 4.85 (m, 1H), 4.05 (t, J=6.82 Hz, 2H), 3.81 (t, J=6.31 Hz, 2H), 3.06 (m, 2H), 2.80 (m, 4H), 2.27 (m, 4H), 1.91 (m, 2H), 1.75-1.47 (m, 16H), 1.44-1.20 (m, 46H), 0.85 (t, J=6.83 Hz, 9H).
Heptadecan-9-yl 8-((3-hydroxypropyl)(8-oxo-8-(undecyloxy)octyl)amino)-octanoate B24. 1H NMR (300 MHz, CDCl3) δ 4.85 (m, 1H), 4.04 (t, J=6.82 Hz, 2H), 3.81 (t, J=6.22 Hz, 2H), 3.04 (m, 2H), 2.86 (m, 4H), 2.26 (m, 4H), 1.93 (m, 2H), 1.75-1.47 (m, 14H), 1.45-1.08 (m, 52H), 0.87 (t, J=6.80 Hz, 9H).
Heptadecan-9-yl 7-((3-hydroxypropyl)(6-(nonyloxy)-6-oxohexyl)amino)-heptanoate B25. 1H NMR (300 MHz, CDCl3) δ 4.85 (m, 1H), 4.05 (t, J=6.83 Hz, 2H), 3.82 (t, J=6.28 Hz, 2H), 3.01 (m, 2H), 2.85 (m, 4H), 2.30 (m, 4H), 1.77-1.47 (m, 18H), 1.40-1.18 (m, 40H), 0.87 (t, J=6.79 Hz, 9H).
Heptadecan-9-yl 8-((6-(heptyloxy)-6-oxohexyl)(3-hydroxypropyl)amino)-octanoate B26. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.06 (t, J=6.86 Hz, 2H), 3.80 (t, J=6.28 Hz, 2H), 2.79 (m, 2H), 2.59 (m, 4H), 2.30 (m, 4H), 1.75-1.33 (m, 18H), 1.31-1.18 (m, 38H), 0.88 (t, J=6.81 Hz, 9H).
Heptadecan-9-yl 8-((3-hydroxypropyl)(6-oxo-6-(undecyloxy)hexyl)amino)-octanoate B27. 1H NMR (300 MHz, CDCl3) δ 4.86 (m, 1H), 4.05 (t, J=6.78 Hz, 2H), 3.80 (t, J=6.36 Hz, 2H), 2.74 (m, 2H), 2.52 (m, 4H), 2.28 (m, 4H), 1.78-1.46 (m, 20H), 1.44-1.18 (m, 44H), 0.88 (t, J=6.83 Hz, 9H).
Di(heptadecan-9-yl) 6,6′-((2-hydroxyethyl)azanediyl)dihexanoate B28. 1H NMR (300 MHz, CDCl3) δ 4.88 (m, 2H), 3.56 (t, 0.1=6.70 Hz, 2H), 2.62 (t, J=6.42 Hz, 2H), 2.50 (t, J=6.64 Hz, 4H), 2.30 (t, J=6.42 Hz, 4H), 1.66 (m, 4H), 1.57-1.36 (m, 12H), 1.36-1.20 (m, 52H), 0.90 (t, J=6.79 Hz, 12H).
Di(heptadecan-9-yl) 7,7′-((2-hydroxyethyl)azanediyl)diheptanoate B29. 1H NMR (300 MHz, CDCl3) δ 4.88 (m, 2H), 3.58 (t, J=6.54 Hz, 2H), 2.64 (t, J=6.02 Hz, 2H), 2.49 (t, J=6.64 Hz, 4H), 2.30 (t, J=6.71 Hz, 4H), 1.62 (m, 4H), 1.58-1.39 (m, 10H), 1.36-1.20 (m, 58H), 0.90 (t, J=6.75 Hz, 12H).
((2-Hydroxyethyl)azanediyl)bis(hexane-6,1-diyl) bis(2-hexyldecanoate) B30. 1H NMR (300 MHz, CDCl3) Q 4.06 (t, J=6.82 Hz, 4H), 3.59 (m, 2H), 2.65 (m 2H), 2.53 (m, 4H), 2.31 (m, 2H), 1.91 (m, 2H), 1.75-1.50 (m, 10H), 1.48-1.30 (m, 12H), 1.30-1.11 (m, 40H), 0.87 (t, J=7.02 Hz, 12H).
7-((2-Hydroxyethyl)(8-oxo-8-(pentadecan-7-yloxy)octyl)amino)heptyl 2-hexyldecanoate B31. 1H NMR (300 MHz, CDCl3) Q 4.06 (t, J=6.80 Hz, 4H), 3.60 (m, 2H), 2.67 (m 2H), 2.54 (m, 4H), 2.29 (m, 2H), 1.70-1.09 (m, 68H), 0.87 (t, J=6.90 Hz, 12H).
((2-Hydroxyethyl)azanediyl)bis(octane-8,1-diyl) bis(2-hexyldecanoate) B32. 1H NMR (300 MHz, CDCl3) Q 4.06 (t, J=6.80 Hz, 4H), 3.62 (m, 2H), 2.82-2.32 (m, 6H), 2.29 (m, 2H), 1.75-1.53 (m, 20H), 1.43 (m, 4H), 1.42-1.20 (m, 50H), 0.87 (t, J=6.96 Hz, 12H).
((3-Hydroxypropyl)azanediyl)bis(hexane-6,1-diyl) bis(2-hexyldecanoate) B33. 1H NMR (300 MHz, CDCl3) Q 4.05 (t, J=6.83 Hz, 4H), 3.79 (t, J=6.21 Hz, 2H), 2.70 (t, J=6.23 Hz, 2H), 2.27 (m, 4H), 2.28 (m, 2H), 1.72 (m, 2H), 1.69-1.49 (m, 12H), 1.49-1.28 (m, 12H), 1.28-1.18 (m, 41H), 0.86 (t, J=6.98 Hz, 12H).
((3-Hydroxypropyl)azanediyl)bis(heptane-7,1-diyl) bis(2-hexyldecanoate) B34. 1H NMR (300 MHz, CDCl3) Q 4.06 (t, J=6.79 Hz, 4H), 3.79 (t, J=6.74 Hz, 2H), 2.63 (t, J=6.79 Hz, 2H), 2.38 (m, 4H), 2.32 (m 2H), 1.73-1.50 (m, 10H), 1.50-32-1.30 (m, 8H), 1.30-1.20 (m, 54H), 0.87 (t, J=6.98 Hz, 12H).
((3-Hydroxypropyl)azanediyl)bis(octane-8,1-diyl) bis(2-hexyldecanoate) B35. 1H NMR (300 MHz, CDCl3) Q 4.06 (t, J=6.86 Hz, 4H), 3.82 (t, J=6.38 Hz, 2H), 3.12-2.50 (m, 6H), 2.32 (m, 2H), 1.87 (m, 2H), 1.69-1.33 (m, 20H), 1.31-1.13 (m, 52H), 0.87 (t, J=6.98 Hz, 12H).
((4-Hydroxybutyl)azanediyl)bis(heptane-7,1-diyl) bis(2-hexyldecanoate) B36. 1H NMR (300 MHz, CDCl3) Q 4.05 (t, J=6.82 Hz, 4H), 3.57 (m, 2H), 2.52 (m, 6H), 2.30 (m 2H), 1.68 (m, 4H), 1.66-1.50 (m, 12H), 1.50-1.18 (m, 56H), 0.87 (t, J=6.98 Hz, 12H).
((4-Hydroxybutyl)azanediyl)bis(octane-8,1-diyl) bis(2-hexyldecanoate) B37. 1H NMR (300 MHz, CDCl3) Q 4.05 (t, J=6.80 Hz, 4H), 3.56 (m, 2H), 2.89-2.38 (m, 6H), 2.28 (m, 2H), 1.75-1.52 (m, 22H), 1.48 (m, 4H), 1.43-1.18 (m, 50H), 0.86 (t, J=6.92 Hz, 12H).
((5-Hydroxypentyl)azanediyl)bis(hexane-6,1-diyl) bis(2-hexyldecanoate) B38. 1H NMR (300 MHz, CDCl3) Q 4.05 (t, J=6.82 Hz, 4H), 3.67 (m, 2H), 2.98 (m, 6H), 2.28 (m, 2H), 1.90-1.75 (m, 2H), 1.68-1.53 (m, 12H), 1.50-1.28 (m, 14H), 1.27-1.06 (m, 42H), 0.87 (t, J=6.98 Hz, 12H).
((5-Hydroxypentyl)azanediyl)bis(heptane-7,1-diyl) bis(2-hexyldecanoate) B39. 1H NMR (300 MHz, CDCl3) Q 4.06 (t, J=6.80 Hz, 4H), 3.64 (t, J=6.69 Hz, 2H), 2.44 (m, 6H), 2.30 (m, 2H), 1.75-1.36 (m, 20H), 1.36-1.19 (m, 44H), 0.87 (t, J=6.98 Hz, 12H).
((5-Hydroxypentyl)azanediyl)bis(octane-8,1-diyl) bis(2-hexyldecanoate) B40. 1H NMR (300 MHz, CDCl3) Q 4.06 (t, J=6.84 Hz, 4H), 3.66 (t, J=6.72 Hz, 2H), 2.82-2.41 (m, 6H), 2.30 (m, 2H), 1.73-1.51 (m, 22H), 1.43 (m, 4H), 1.40-1.19 (m, 52H), 0.87 (t, J=7.02 Hz, 12H).
Di(heptadecan-9-yl) 8,8′-((2-hydroxyethyl)azanediyl)dioctanoate B41. MS (ESI) m z: 822.6 [M+H]+.
Heptadecan-9-yl (Z)-8-((2-hydroxyethyl)(6-(non-2-en-1-yloxy)-6-oxohexyl)-amino)octanoate B44. MS (ESI) m z: 680.2 [M+H]+.
((2-(2-Methoxyethoxy)ethyl)azanediyl)bis(hexane-6,1-diyl) bis(2-hexyldecanoate) B46. MS (ESI) m z: 796.7 [M+H]+.
Di(pentadecan-7-yl) 8,8′-((2-hydroxyethyl)azanediyl)dioctanoate B47. MS (ESI) m z: 766.8 [M+H]+.
The following compounds are prepared similarly according to the synthetic procedures or methodologies exemplified herein.
Pentadecan-7-yl 8-((2-hydroxyethyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)-hexyl)amino)octanoate A8.
1,1,1,17,17,17-Hexafluoroheptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)hexyl)amino)octanoate A9.
8,8′-((3-Hydroxypropyl)azanediyl)bis(N-hexyl-N-octyloctanamide) A11.
((3-Hydroxypropyl)azanediyl)bis(hexane-6,1-diyl) bis(hexyl(octyl)carbamate) A12.
N-(3-Hydroxypropyl)-N,N-di(7-(pentadecan-7-oxycarbonyloxy)heptyl)amine A13.
((((3-Hydroxypropyl)azanediyl)bis(propane-3,1-diyl))bis(oxy))bis(ethane-2,1-diyl)bis(2-hexyldecanoate) A14.
Di(pentadecan-7-yl) 3,3′-((((3-hydroxypropyl)azanediyl)bis(propane-3,1-diyl))bis(oxy))dipropionate A15.
Bis(1,1,1,15,15,15-hexafluoropentadecan-7-yl) 7,7′-((3-hydroxypropyl)-azanediyl)diheptanoate A16.
1,1,1,15,15,15-Hexafluoropentadecan-7-yl 8-((3-hydroxypropyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)hexyl)amino)octanoate A17.
Pentadecan-7-yl 8-((3-hydroxypropyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)-hexyl)amino)octanoate A18.
1,1,1,17,17,17-Hexafluoroheptadecan-9-yl 8-((3-hydroxypropyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)hexyl)amino)octanoate A19.
Heptadecan-9-yl 8-((3-hydroxypropyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)-hexyl)amino)octanoate A20.
8,8′-((4-Hydroxybutyl)azanediyl)bis(N-hexyl-N-octyloctanamide) A21.
((4-Hydroxybutyl)azanediyl)bis(hexane-6,1-diyl) bis(hexyl(octyl)carbamate) A22.
N-(4-Hydroxybutyl)-N,N-di(7-(pentadecan-7-oxycarbonyloxy)heptyl)amine A23.
((((4-Hydroxybutyl)azanediyl)bis(propane-3,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-hexyldecanoate) A24.
Di(pentadecan-7-yl) 3,3′-((((4-hydroxybutyl)azanediyl)bis(propane-3,1-diyl))bis(oxy))dipropionate A25.
Bis(1,1,1,15,15,15-hexafluoropentadecan-7-yl) 7,7′-((4-hydroxybutyl)-azanediyl)diheptanoate A26.
1,1,1,15,15,15-Hexafluoropentadecan-7-yl 8-((4-hydroxybutyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)hexyl)amino)octanoate A27.
Pentadecan-7-yl 8-((4-hydroxybutyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)-hexyl)amino)octanoate A28.
1,1,1,17,17,17-Hexafluoroheptadecan-9-yl 8-((4-hydroxybutyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)hexyl)amino)octanoate A29.
Heptadecan-9-yl 8-((4-hydroxybutyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)-hexyl)amino)octanoate A30.
8,8′-((5-Hydroxypentyl)azanediyl)bis(N-hexyl-N-octyloctanamide) A31.
((5-Hydroxypentyl)azanediyl)bis(hexane-6,1-diyl) bis(hexyl(octyl)carbamate) A32.
N-(5-Hydroxypentyl)-N,N-di(7-(pentadecan-7-oxycarbonyloxy)heptyl)amine A33.
((((5-Hydroxypentyl)azanediyl)bis(propane-3,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-hexyldecanoate) A34.
Di(pentadecan-7-yl) 3,3′-((((5-hydroxypentyl)azanediyl)bis(propane-3,1-diyl))bis(oxy))dipropionate A35.
Bis(1,1,1,15,15,15-hexafluoropentadecan-7-yl) 7,7′-((5-hydroxypentyl)-azanediyl)diheptanoate A36.
1,1,1,15,15,15-Hexafluoropentadecan-7-yl 8-((5-hydroxypentyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)hexyl)amino)octanoate A37.
Pentadecan-7-yl 8-((5-hydroxypentyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)-hexyl)amino)octanoate A38.
1,1,1,17,17,17-Hexafluoroheptadecan-9-yl 8-((5-hydroxypentyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)hexyl)amino)octanoate A39.
Heptadecan-9-yl 8-((5-hydroxypentyl)(6-oxo-6-((11,11,11-trifluoroundecyl)oxy)-hexyl)amino)octanoate A40.
N-(2-Hydroxyethyl)-N,N-di(5-(pentadecan-7-oxycarbonyloxy)pentyl)amine A41.
N-(2-Hydroxyethyl)-N,N-di(7-(heptadecan-9-oxycarbonyloxy)heptyl)amine A42.
((((2-Hydroxyethyl)azanediyl)bis(propane-3,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-hexyldecanoate) A43.
Di(pentadecan-7-yl) 3,3′-((((2-hydroxyethyl)azanediyl)bis(propane-3,1-diyl))bis(oxy))dipropionate A44.
Di(pentadecan-7-yl) 10-(2-hydroxyethyl)-4,7,13,16-tetraoxa-10-azanonadecane-dioate A45.
Heptadecan-9-yl (6-((4-hydroxybutyl)(6-(((undecyloxy)carbonyl)amino)hexyl)-amino)hexyl)carbamate A47.
((((2-Hydroxyethyl)azanediyl)bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-hexyldecanoate) A50.
Di(heptadecan-9-yl) 10-(2-hydroxyethyl)-4,7,13,16-tetraoxa-10-azanonadecane-dioate A51.
8,8′-((2-Hydroxyethyl)azanediyl)bis(N-hexyl-N-octyloctanamide) A52.
Heptadecan-9-yl 8-((2-hydroxyethyl)(3-oxo-4,7,10,13-tetraoxatetracosyl)amino)-octanoate A53.
Heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(2-(2-(pentyloxy)ethoxy)ethoxy)-hexyl)amino)octanoate A54.
Di(heptadecan-9-yl) 8,8′-((4-hydroxybutyl)azanediyl)dioctanoate B42.
Di(heptadecan-9-yl) 8,8′-((3-(dimethylamino)propyl)azanediyl)dioctanoate B43.
Di(heptadecan-9-yl) 8,8′-((2-hydroxyethyl)azanediyl)dioctanoate B45.
5-((2-Hydroxyethyl)(7-((2-octyldecanoyl)oxy)heptyl)amino)pentyl dodecanoate B48.
The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.
This application claims the benefit of the priority of U.S. Provisional Application Nos. 63/269,397, filed Mar. 25, 2022, and 63/364,020, filed May 2, 2022; the disclosure of each of which is incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2023/064282 | 3/14/2023 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63364020 | May 2022 | US | |
| 63269397 | Mar 2022 | US |
